DAP12 (DNAX Activation Protein 12) is indicated to be a transmembrane protein containing an activation motif, ITAM, which binds to ZAP-70 or Syk through phosphorylation. It is known that DAP12 is encoded by a single-copy gene located on the 19q13.1 in humans and also exists in mice. It is also known that mRNAs of the DAP12 are largely expressed in monocytes, dendritic cells, and natural killer cells, and that DAP12 is not only involved in activated signaling of a KAR group, but also associates with a human signal regulatory protein (SIRP) β1, a human or a murine myeloid DAP12-associating lectin (MDL)-1, and a triggering receptor expressed on myeloid cells (TREM). It is reported that DAP12 also associates with KAR molecules, which belong to the C-type lectin family, such as CD94/NKG2C and the like, and performs its function (Immunity 8, 693-701, 1998; J. Immunol. 161, 7-10, 1998; J. Immunol. 160, 4148-52, 1998).
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease (Suppl. 232, 1-173, 1972; Acta Pathol. Jpn. 23, 539-558, 1973; J. Med. Genet. 34, 753-757, 1977) is a central nervous system disorder found in Japan and Finland. In addition to the formation of bone cysts, patients of Nasu-Hakola disease develop psychotic symptoms, such as personality changes, inevitably progressing to pre-senile dementia. The mutation found in Finnish patients is a 5.3 kb deletion in the DAP12 [KARAP (Killer activating receptor associated protein)/TYROBP (protein tyrosine kinase binding protein)] locus, while another defect in Japanese patients is a single-nucleotide deletion in the third exon of the gene. Both are known to be caused by the loss of function of DAP12, a membrane adaptor protein (J. Immunol. 158, 5083-5086, 1997; Nature 391, 703-707, 1998) found initially in the immune system (Nature Genet. 25, 357-361, 2000). However, it has not yet known whether psychotic symptoms are caused by the deficiency of DAP12.
On the other hand, in an animal model of dementia, only methods for inducing cerebral ischemia or accumulating amyloid protein have been developed, and the utility values of such model animals as a base for analyzing the mechanisms progressing to dementia and for preventing the progression of dementia have not been efficient. It has been known in recent years that the deficiency of DAP12 induces the onset of neuropsychiatric disorders progressing to juvenile dementia called Nasu-Hakola disease (Nature Genet. 25, 357-361, 2000). However, the fundamental cause has not been verified, and it is not known whether the frontal lobe- and thalamus-specific dysmyelination occurs in DAP12 deficient mice that show symptoms of schizophrenia.
The aforementioned Nasu-Hakola disease is a recessive hereditary disease, which is fatal and inevitably progressing to presenile dementia following the formation of bone cysts and neuropsychiatric disorders. The object of the present invention is to provide the following: a non-human animal model of oligodendrocyte developmental disorder whose DAP12 (DNAX Activation Protein 12) gene function is deficient on its chromosome; a screening method for a developmental promoter or a developmental suppressor of oligodendrocytes, or, a promoter or a suppressor of myelinogenesis, wherein the non-human animal model of oligodendrocyte developmental disorder is used; a screening method for a therapeutic agent for neuropsychiatric disorders; a diagnostic method for neuropsychiatric disorders, which enable to develop a preventive method for the progress of neuropsychiatric disorders and a therapeutic method for neuropsychiatric disorders by analyzing the mechanisms progressing to neuropsychiatric disorders such as Nasu-Hakola disease, dementia, schizophrenia, schizotypal personality disorders, obsessive-compulsive disorders, Huntington's disease and Tourette's syndrome, etc.
The present inventors have analyzed the physiological function of DAP12, generated a mouse whose DAP12 gene function is deficient on its chromosome, namely a DAP12 knockout mouse, and examined the brain. The present inventors have found that demyelination, namely myelination disorder including hypomyelinosis, can be seen particularly in the frontal head and thalamus, and that this disorder is attributed to the inhibition of differentiation, development, intracerebral transfer in the cell due to the deficiency of DAP12 in oligodendrocytes that plays a role of myelinogenesis. The present inventors have further found that deficiency can be seen in the reflective power, despite that muscle and the like are normal by the behavioral analysis of the above-mentioned DAP12 knockout mouse, and clarified that psychotic symptoms similar to schizophrenia can be seen with aging.